The efficient synthesis of novel estradiol‐based A‐ring‐fused oxazole derivatives,
which can be considered as benzoxazole‐steroid domain‐integrated hybrids containing
a common benzene structural motif, is described. The target compounds were prepared
from steroidal 2‐aminophenol precursors by heterocycle formation or functional group
interconversion (FGI) strategies. According to 2D projection‐based t‐distributed stochastic
neighbor embedding (t‐SNE), the novel molecules were proved to represent a new chemical
space among steroid drugs. They were characterized based on critical physicochemical
parameters using in silico and experimental data. The performance of the compounds
to inhibit cell proliferation was tested on four human cancer cell lines and non‐cancerous
cells. Further examinations were performed to reveal IC50 and lipophilic ligand efficiency
(LLE) values, cancer cell selectivity, and apoptosis‐triggering features. Pharmacological
tests and LLE metric revealed that some derivatives, especially the 2‐(4‐ethylpiperazin‐1‐yl)oxazole
derivative exhibit strong anticancer activity and trigger the apoptosis of cancer
cells with relatively low promiscuity risk similarly to the structurally most closely‐related
and intensively studied anticancer agent, 2‐methoxy‐estradiol.
